Huntington disease

New study challenges the hypothesis of glutamate transporter dysfunction in Huntington disease

Glutamate transporter function in the striatal synapses might be intact or even accelerated in Huntington disease (HD), according to new observations in mouse brain slices. The finding challenges the prevailing hypothesis of impaired glutamate transporter function in HD: previous studies, conducted mostly in isolated synaptosomes, have suggested that impaired glutamate uptake and the resulting excitotoxity are involved in the pathophysiology of HD.

Glutamate clearance in the striatal synapses requires astrocytic glutamate transporter and neuronal EAAC1 (excitatory amino acid carrier 1) function. iGluSnFR response reflects the extracellular glutamate levels sensed by neurons. Credit: Adapted with permission from Macmillan Publishers Ltd © Parsons, M. P. et al. Nat. Commun. 7, 11251 (2016)

Matthew Parsons, Lynn Raymond and colleagues visualized glutamate release and clearance in striatal slices from transgenic HD model mice and control mice with optogenetic iGluSnFR (intensity-based glutamate-sensing fluorescent reporter) probe. Using acute brain slices enabled the researchers to preserve synapses and local connections between the striatal neurons, thereby mimicking the physiological conditions in the brain more closely than in experiments conducted with isolated synapses or membranes.

“Glutamate clearance in the HD model mice was normal, or even accelerated”

“Glutamate clearance in the HD model mice was normal, or even accelerated,” says Parsons. Previous biochemical and molecular studies, conducted using the same strains of HD model mice have suggested glutamate transporter function to be impaired in HD. This impairment is thought to exacerbate glutamate excitotoxicity and neuronal death triggered by extrasynaptic NMDA receptor activity.

“The conclusions drawn from prior biochemical studies have been extrapolated to produce a widespread and well-accepted belief that glutamate clearance is slow in the HD brain and that this impairment contributes to disease pathogenesis,” comments Raymond. The new results indicate that glutamate transporter function in HD could be sufficient to maintain normal levels of glutamate clearance; therefore, targeting glutamate transporters in HD may be of limited therapeutic value. “Instead of increasing glutamate transporter function to accelerate glutamate clearance beyond the normal rate, targeting NMDA receptors themselves, and particularly those located at extrasynaptic sites, could provide a better strategy,” Raymond concludes.

References

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    Parsons, M. P. et al. Real-time imaging of glutamate clearance reveals normal striatal uptake in Huntington disease mouse models. Nat. Commun. 7, 11251 (2016)

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Malkki, H. New study challenges the hypothesis of glutamate transporter dysfunction in Huntington disease. Nat Rev Neurol 12, 251 (2016). https://doi.org/10.1038/nrneurol.2016.58

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